1. Field of the Invention
The present invention relates to an improved process for preparing imidazo[1,2-a]pyridine-3-N,N-dialkylacetamides.
The present invention relates to an improved synthesis of imidazo[1,2-a]pyridine-3-N,N-dialkylacetamides. The utility of compounds of this general structure is described extensively in the literature and best represented by the well known pharmaceutical, zolpidem tartrate, which is distributed commercially for sleep disorders.
2. Description of the Related Art
Almost all previously described methods of synthesis have proceeded through the initial formation of the required imidazo[1,2-a]pyridine followed by the attachment of a suitable derivative on the 3-position and subsequent conversion to the desired acetamide derivative. Thus, U.S. Pat. No. 4,794,185 describes a method of formation of compound (I), see below, via reaction of the aldehyde prepared in situ by acid hydrolysis from N,N-dimethyl-2,2-dimethoxyacetamide, isolation of the 3-substituted derivative (III), conversion of the hydroxyl group to the chloride with thionyl chloride and subsequent reduction of the chloro derivative to the imidazo[1,2-a]pyridine-3-N,N-dialkylacetamide derivative with sodium borohydride. This process suffers from the fact that it is difficult to obtain a suitable hydrolysis product of N,N-dimethyl-2,2-dimethoxyacetamide in situ and thus the reaction can not be taken to completion. Also the procedure is very laborious and usually results in low yields. Separation of the starting imidazo[1,2-a]pyridine from the reaction product has also proven difficult. On top of that, the formation of the chloro derivative and reduction to the acetamide with sodium borohydride produces low yields which make the product difficult to purify and the addition of sodium borohydride directly to an acidic media produces a hazard in that hydrogen gas is rapidly evolved. EP 50,563 describes a process in which 6-methyl-2-(4-methylphenyl)-imidazo[1,2-a]pyridine is reacted to form 3-(N,N-dimethylaminoethyl)-6-methyl-2-(4-methylphenyl)-imidazo[1,2-a]pyridine. This compound is then treated with methyl iodide, displaced with cyanide. The resulting cyano compound can then be converted to the desired derivative in several steps. Again this is a very laborious procedure and produces low yields.
Other potentially useful derivatives and other methods for the formation of these derivatives have been reported. U.S. Pat. No. 6,407,240 B1 describes the synthesis proceeding through the corresponding ester which can then be converted to desired compound in three steps. This procedure uses undesirable chlorinated solvents in several steps.
The highly crystalline, stable hemi-hydrate of dimethylglyoxylamide (II), see below, has been reported in GB 793,807 but the use of this compound in condensation reactions with imidazo[1,2-a]pyridine has not been demonstrated.
Thus, prior methods of preparation of (I) require many steps, occur in low yield, use toxic solvents and involve complicated procedures. Therefore, there is a need for a more economic and simpler commercial synthesis.